The overriding goal of R01DA013324 is to investigate the host genetic basis for spontaneous clearance of hepatitis C virus (HCV) infection in persons with and without HIV. After infection, HCV either replicates for decades at high levels or is spontaneously cleared. This discrete outcome is of paramount public health importance because persons who have persistent infection (but not those who clear) have a markedly increased risk of liver failure or cancer, and in 2007 in the US, HCV surpassed HIV as a cause of death. There is overwhelming evidence that host genetic differences explain why some persons clear infection and others have viral persistence. The two outcomes occurred even when persons were accidently infected with the same viral inoculum, and persons of African descent are 5 times less likely to clear than Caucasians. To investigate the genetic basis for HCV clearance, we compare DNA sequences of persons with HCV antibodies but not HCV RNA (clearance) to those with both antibodies and RNA (persistence). Because of shared transmission routes HIV/HCV coinfection is common, and our studies also focus on HIV allowing comparisons of mechanisms of control of two leading chronic viral infections. Similarities and differences in the genetic determinants of control inform efforts to combat each viral infection and may also shed insights into post-viral inflammatory syndromes. We, and our collaborators, have already made multiple important discoveries that have major implications with HCV and possibly HIV vaccine development and disease control. However, important questions remain and can now be answered due to technological advances in genetic testing and the infrastructure of our HCV clearance research consortium.